Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria: a multicentre randomized control trial

Michael Nambozi, Modest Mulenga, Tinto Halidou, Harry Tagbor, Victor Mwapasa, Linda Kalilani Phiri, Gertrude Kalanda, Innocent Valea, Maminata Traore, David Mwakazanga, Yves Claeys, Céline Schurmans, Maaike De Crop, Joris Menten, Raffaella Ravinetto, Kamala Thriemer, Jean-Pierre Van Geertruyden, Theonest Mutabingwa, Umberto D'Alessandro, Pregact Group, Michael Nambozi, Modest Mulenga, Tinto Halidou, Harry Tagbor, Victor Mwapasa, Linda Kalilani Phiri, Gertrude Kalanda, Innocent Valea, Maminata Traore, David Mwakazanga, Yves Claeys, Céline Schurmans, Maaike De Crop, Joris Menten, Raffaella Ravinetto, Kamala Thriemer, Jean-Pierre Van Geertruyden, Theonest Mutabingwa, Umberto D'Alessandro, Pregact Group

Abstract

Background: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided.

Design: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4-6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data.

Discussion: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative '-value-' compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.

Trial registration: ClinicalTrials.gov NCT00852423.

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